7-.beta.-Acetylthio-17.beta.-(2-carboxyethyl)-17.beta.-hydroxyandrost-4-en- 3-one lactone (spironolactone) is a diuretic marketed both alone and with another diuretic (hydrochlorothiazide). See the Physicians Desk Reference 1978, pages 1537 and 1538, respectively.
A number of methods for the synthesis of spironolactone are known, see for example, U.S. Pat. Nos. 3,013,012, 3,413,288, 3,682,894, 3,847,906, 3,883,512, 3,894,006, 3,897,417, 3,900,467, 3,966,714, 4,057,543 and 4,211,701. These patents report multistep processes for the conversion of a steroidal-17-ketone to the 17.alpha.-(2-carboxyethyl)-17.beta.-hydroxyandrost-4-en-3-one lactone (hereinafter referred to as 17-spirolactone). The transformation of 17-spirolactone to the 17.alpha.-(2-carboxyethyl)-17.beta.-hydroxyandrosta-4,6-dien-3-one lactone (hereinafter referred to as .DELTA.4,6-lactone) can be performed in a number of ways, see U.S. Pat. No. 3,452,008 for the transformation of a 19-nor lactone to the corresponding 19-nor-.DELTA.4,6-lactone. In addition, U.S. Pat. No. 2,900,383 (Example 2) discloses the transformation of 17-spirolactone to the .DELTA.4,6-lactone. U.S. Pat. No. 4,211,701 discloses the transformation of 17-spirolactone to the 3-acyloxy-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxyandrosta-3,5-diene lactone, bromination to give 6-bromo-17.alpha.-(2-carboxyethyl)-17.beta. -hydroandrost-4-ene-3-one lactone and heating in the presence of calcium carbonate to give 17.alpha.-(2-carboxyethyl)-17.beta.-hydroxyandrosta-4,6-dien-3-one lactone (.DELTA.4,6-lactone).
The .DELTA.4,6-lactone is transformed to spironolactone by methods well known to those skilled in the art, in particular, see U.S. Pat. No. 3,013,012 (Example 3) and U.S. Pat. No. 4,211,701 (Col. 8, lines 15-33).
U.S. Pat. No. 4,267,106, German Offenlegungsschrift No. 2,932,924, and British Application No. 2,028,825 describe a single step process for the conversion of a 3-protected androst-5-ene-17-one, to 17.beta.-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone (17-spirolactone) and 17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone by reacting the ketone with organophosphorous compounds such as allyl phosphate bis-methyl and bis-diethyl-amide, allyl dimethyl phosphate and allyl diethyl phosphate, in an organic solvent at a temperature between -90.degree. and +50.degree. C. and in the presence of a suitable strong base, for example, alkyl- or aryl-lithium compounds.
See also Sturtz, et al., Lactonization at 17.beta.-position of steroids, Synthesis, 289-291, April 1980. Sturtz describes the direct synthesis of andronolactone and its methyl homolog by reaction of the O-tetrahydropyranyl derivative of 3.beta.-hydroxy-17-oxo-5-androstene with the dilithio derivative obtained from allyl or 2-methylallyl tetramethylphosphorodiamidate and 2 equiv of butyllithium.
Two groups of investigators have shown that 2-(disubstituted amino)-2-butenonitrile, on deprotonation, gives an anion which preferentially adds electrophiles exclusively in the .gamma.-position, see Toye, et al., J.A.C.s., 97, 2276 (1975); Lesin, et al., Tetra. Lett., 2835 (1979); H. Albrecht, et al., Synthesis, 512 (1975) and H. Albrecht, et al., Synthesis, 336 (1977).